Method of treating inflammation

ABSTRACT

The present invention relates to the use of compounds of general formula (I) as ligands to the melanocortin receptors and/or for treatment of disorders in the melanocortin system: 
                         
wherein X is H or OH; R 1 , R 2 , R 3 , R 4  and R 5  are the same or different and are selected from hydrogen, halogen, alkyl having 1 to 5 carbon atoms, electron donor groups such as alkoxy having 1-5 carbon atoms or hydroxy, electron acceptor groups selected from cyano, nitro, trifluoroalkyl or amide; alkylamino, benzoyloxy, nitroxy, phenyl or sulpho; and the pharmacologically active salts thereof.

This application is a continuation of U.S. patent application Ser. No.13/426,096, filed Mar. 21, 2012, which is a continuation application ofpending U.S. patent application Ser. No. 11/639,190, filed Dec. 15,2006, which has issued as U.S. Pat. No. 8,148,429 on Apr. 3, 2012, whichis a continuation of Ser. No. 10/343,325, filed Jun. 23, 2003, which isa PCT National Stage Application of PCT/GB2001/003534 filed Aug. 7, 2001(of which the entire disclosure of the pending, prior application ishereby incorporated by reference).

The present invention relates to the use of benzylideneaminoguanidinesand hydroxyguanidines for the treatment of obesity, anorexia,inflammation, mental disorders and other diseases associated with themelanocortin receptors or related systems, e.g. the melanocytestimulating hormones.

A number of large linear and cyclic peptides are known in the art whichshow high specific binding to melanocortin (MC) receptors. The agonisticand/or antagonistic properties of these peptides are also known. See forexample “Melanocortin Receptor ligands and methods of using same” byDooley, Girten and Houghten (WO99/21571). There remains, however, a needto provide low molecular weight compounds showing agonistic orantagonistic properties to the melanocortin receptors.

Previously known in the art are hydroxyguanidines (e.g. WO98/23267),which have proven activity against xanthine oxidase/xanthinedehydrogenase enzymes. Other compounds known in the art arebenzylideneamino guanidines which have shown anti-depressive effects(U.S. Pat. No. 4,060,640). Other examples of pharmacologically activeguanidines known in the art are described in U.S. Pat. No. 3,982,020 andGB 1223491. Other application areas are also known in the art and aredescribed in U.S. Pat. No. 3,896,332, DE 1165013, and U.S. Pat. No.3,941,825. Guanabenz is compound which is well known in the art as anantihypertensive drug (US Pharmacopeia, 1999, The United StatesPharmacopeial Convention, Inc, ISBN 1-889788-03-1). Whilst Guanabenzmight appear to be structurally similar to the compounds in the presentinvention, it shows no affinity to the melanocortin receptors. Thereforeit is very surprising that the benzylideneamino guanidine compounds inthe present invention show affinity to the melanocortin receptors asagonist and/or antagonists.

One aspect of the present invention is therefore to provide lowmolecular weight compounds showing activity on melanocortin receptorsand which may be taken up after per oral administration and which maypenetrate well through the blood brain barrier.

The present invention provides the use of compounds of the generalformula (I) as ligands to the melanocortin receptors and/or fortreatment of disorders in the melanocortin system:

wherein X is H or OH;R₁, R₂, R₃, R₄ and R₅ are the same or different and are selected fromhydrogen, halogen, alkyl having 1 to 5 carbon atoms, electron donorgroups such as alkoxy having 1-5 carbon atoms or hydroxy, electronacceptor groups selected from cyano, nitro, trifluoroalkyl or amide;alkylamino, benzoyloxy, nitroxy, phenyl or sulpho; and thepharmacologically active salts thereof.

When used in the foregoing definitions, the term alkyl is meant toinclude straight or branched chain hydrocarbon groups as well asalicyclic groups; the term alkoxy is meant to include straight orbranched chain alkoxy groups or heterocyclic groups; and the termhalogen includes fluoro, chloro, bromo and iodo.

Preferably, the “alkyl having 1 to 5 carbon atoms” is a lower alkyl suchas methyl, ethyl, propyl or iso-propyl.

Preferably, the “alkoxy having 1 to 5 carbon atoms” is a lower alkoxysuch as methoxy, ethoxy, propoxy or iso-propoxy.

Preferably, the halogen is fluoro or chloro.

Preferably, the trifluoroalkyl is trifluoromethyl, trifluoroethyl,trifluoropropyl or trifluoroisopropyl.

The term “alkylamino” refers preferably to groups having 2-6 carbonatoms, particularly dialkylamino groups, and most preferablydimethylamino or diethylamino.

Two or more of R₁-R₅ may be linked by a linker group such as—O—(CH₂)_(n)—O—, where n is preferably 1, 2 or 3. Most preferably thelinker is a methylenedioxy group, particularly preferably a 2,3- 3,4- or4,5-methylenedioxy group.

Further preferred compounds are those wherein R₁ is nitroxy or sulpho;R₃ is phenyl; and R₁, R₂ and R₃ are all benzoyloxy.

Particularly preferred compounds are those wherein 1 or 2 of R₁, R₂, R₃,R₄ and R₅ are H.

The compounds of formula (I) have basic properties and, consequently,they may be converted to their therapeutically active acid additionsalts by treatment with appropriate physiologically acceptable acids,e.g. inorganic acids such as hydrochloric, hydrobromic, hydroiodic,sulphuric, nitric and phosphoric acid, or organic acids such as acetic,propanoic, glycolic, lactic, malonic, succinic, fumaric, tartaric,citric, pamoic or para-toluene-sulphonic acid.

Conversely, the salt form may be converted into the free base form bytreatment with alkali.

The present invention relates the use of benzylideneaminoguanidines andhydroxyguanidines. Some of the compounds of the present invention havebeen biologically tested in the melanocortin system and havesurprisingly been shown to be capable of binding to melanocortinreceptors as well as showing activity in functional assays.

Some of the compounds of the present invention are either agonists orantagonists of a specific MC-receptor or of a number of MC-receptors,e.g. MC1, MC3, MC4 or/and MC5 receptors. The MC-receptors belong to theclass of G-protein coupled receptors which are all built from a singlepolypeptide forming 7 transmembrane domains. Five such receptors types,termed MC1, MC2, MC3, MC4 and MC5, have been described. The MCreceptor's signaling is mainly mediated via cAMP but also other signaltransduction pathways are known. They are distinctly distributed in thebody.

MC-receptors are linked to a variety of physiological actions that arethought to be mediated by distinct subtypes of the MC-receptors. In manycases, however, it is not entirely clear which of the subtypes isresponsible for the effect.

It has long been known that MSH-peptides may affect many differentprocesses such as motivation, learning, memory, behaviour (includingfeeding and sexual), inflammation (including immunostimulatory andimmunosuppressive), body temperature, pain perception, blood pressure,heart rate, vascular tone, brain blood flow, trophic effects indifferent organs, nerve growth, placental development, endocrine andexocrine functions, aldosterone synthesis and release, thyroxin release,spermatogenesis, ovarian weight, prolactin and FSH secretion, effects onother hormones, uterine bleeding in women, sebum and pheromonesecretion, blood glucose levels, intrauterine foetal growth, as well asother events surrounding parturition and natriuresis (Eberle, A N: Themelanotropins: Chemistry, physiology and mechanisms of action. Basel:Karger, Switzerland. 1988, ISBN 3-8055-4678-5; Gruber, and Callahan, Am.J. Physiol. 1989, 257, R681-R694; De Wildt et al., J. CardiovascularPharmacology. 1995, 25, 898-905), as well as inducing natriuresis (Linet al., Hypertension. 1987, 10, 619-627).

It is also well-known that the immunomodulatory action of α-MSH includesboth immunostimulatory and immunosuppressive effects. Several studieshave shown that α-MSH antagonizes the effects of pro-inflammatorycytokines such as IL-1α, IL-1β, LL-6 and TNFα, and induces theproduction of the anti-inflammatory cytokine, IL-10 (for review seeCatania & Lipton, 1993).

Eating behaviour is regulated by a complex network of physiologicalregulatory pathways that involve both the central nervous system andperipheral sites. Factors such as leptin, insulin, NPY (neuropeptide Y),orexins, CRF (Corticotropin-Releasing Factor, release hormone) andmelanocortic peptides (Schwartz; Nature Medicine 1998, 4, 385-386) areknown to control the amount of food intake both during short and longterm, which may affect body weight, body fat mass and growth rate.Recent studies have shown a role of MC-receptors, especially the MC4receptor, for control of food intake, and there is evidence indicatingthat the melanocortins and the MC4 receptor are important factorsdownstream of leptin. Intracerebroventricular injections of themelanocortic peptides α-MSH and ACTH(1-24) have been shown to markedlyinhibit feeding (Poggioli et al., Peptides, 1986, 7, 843-848; Vergoni etal., Neuropeptides, 1986, 7, 153-158).

The MC5-receptor has recently been attributed a role in control ofexocrine gland function (van der Kraan, et al., Endocrinol. 1998, 139,2348-2355; Chen et al., Cell. 1997, 91, 789-798).

In addition, the melanocortic peptides have distinct effects on sexualfunctions in that they cause erection in males (Donovan, Psychol. Med.1978, 8, 305-316), presumably mediated by a central agonistic effect ofthe peptide on MC-receptors. It has also been shown that a MC-receptorblocker could inhibit the erectogenic effect of melanocortic peptides(Vergoni et al., Eur. J. Pharmacol, 1998, 362; 95-101).

Compounds of formula (I) and/or their pharmaceutically acceptable saltshave valuable pharmacological properties, making them useful for thetreatment of mental disorders such as psychoses, depression, anxiety,senile dementia, Alzheimer's disease, drug abuse disorders and eatingdisorders such as anorexia and bulimia.

Compounds of formula (I) and/or their pharmaceutically acceptable saltshave valuable pharmacological properties, making them useful for thetreatment of dysfunctions of the endocrine system and other hormonalsystems such as excessive menstruations, endometriosis, events relatedto parturition, dysfunctions related to prolactin, dysfunctions relatedto growth hormone, dysfunctions related to testosterone, dysfunctionsrelated to estrogen, dysfunctions related to glucocorticoids,dysfunctions related to luteinizing hormone and follicle stimulatinghormone, inducing abortion, for prevention of abortion and/or fortreatment of events related to parturition.

Compounds of formula (I) and/or their pharmaceutically acceptable saltshave valuable pharmacological properties, making them useful for thetreatment of sexual functions/dysfunctions such as inducing erection inman, to induce erection in animal breeding, to stimulate intercourse inanimals which are difficult to mate, in particular rare species orvaluable strains, pets, cats, dogs, horses or to reduce sexual behaviourin animals, e.g. for pets, cats etc., to treat impotence and disordersrelated to sexual drive, including lack of sexual drive or abnormalsexual drive in both men and women.

Compounds of formula (I) and/or their pharmaceutically acceptable saltshave valuable pharmacological properties, making them useful for thetreatment of inflammation such as inflammations related to theproduction of nitric oxide, inflammation related to increased amounts(upregulated amounts) of inducible nitric oxide synthase, inflammationrelated to activation of transcriptional activators, inflammationrelated to nuclear factor kappa beta, inflammation related tomacrophages, neutrophils, monocytes, keratinocytes, fibroblasts,melanocytes, pigment cells and endothelial cells, inflammation relatedto increased production and/or release of inflammatory cytokines, suchas e.g. interleukins, in particular interleukin 1 (IL-1), interleukin 6(IL-6) and tumor necrosis factor α (TNF-α).

In the present specification, “increased production” refers to increasedformation, increased release, or increased amount of an endogenouscompound locally, regionally or systemically in a patient compared tothe amount of said endogenous compound in a healthy individual. In thepresent specification, “upregulated” refers to an increased activity oramount of the compound compared with that in a healthy individual.

In the present specification, “decreased production” refers to decreasedformation, decreased release, or decreased amount of an endogenouscompound in a patient compared to the amount of said endogenous compoundin a healthy individual. In the present specification, “downregulated”refers to a decreased activity or amount of the compound compared withthat in a healthy individual.

In particular, positive treatment effects or preventive effects may beseen in conditions where inflammation or an inflammatory-like conditionis caused by or being associated with one or more of the following:allergy, hypersensitivity, bacterial infection, viral infection,inflammation caused by toxic agent, fever, autoimmune disease, radiationdamage by any source including UV-radiation, X-ray radiation,γ-radiation, α- or β-particles, sun burns, elevated temperature ormechanical injury. Moreover, inflammation due to hypoxia, which isoptionally followed by reoxygenation of the hypoxic area, is typicallyfollowed by severe inflammation, which condition may be positivelyaffected by treatment with a compound of the invention.

In very specific embodiments of the invention, a compound of theinvention may be administered for the prevention or therapeutictreatment of inflammatory diseases of the skin (including the dermis andepidermis) of any origin, including skin diseases having an inflammatorycomponent. Specific examples of this embodiment of the invention includetreatment of contact dermatitis of the skin, sunburns of the skin, burnsof any cause, and inflammation of the skin caused by chemical agents,psoriasis, vasculitis, pyoderma gangrenosum, discoid lupuserythematosus, eczema, pustulosis palmo-plantaris, and phemphigusvulgaris.

Also comprised by the invention is the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of an inflammatory disease in the abdomen, including anabdominal disease having an inflammatory component. Specific examples ofthe treatment of such a disease with a compound of the invention aregastritis, including one of unknown origin, gastritis perniciosa(atrophic gastritis), ulcerous colitis (colitis ulcerosa), morbus Crohn,systemic sclerosis, ulcus duodeni, coeliac disease, oesophagitis andulcus ventriculi.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of systemic or general and/or local immunological diseases,including those of an autoimmune nature, and other inflammatory diseasesof a general nature. Specific examples include treatment of rheumatoidarthritis, psoriatic arthritis, systemic sclerosis, polymyalgiarheumatica, Wegener's granulomatosis, sarcoidosis, eosinophilicfasceitis, reactive arthritis, Bechterew's disease, systemic lupuserythematosus, arteritis temporalis, Behcet's disease, morbus Burger,Good Pastures' syndrome, eosinophilic granuloma, fibromyalgia, myositis,and mixed connective tissue disease. Included therein is also arthritis,including arthritis of unknown origin.

Further included in the invention is administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of a disease of the peripheral and/or central nervous systemrelated to inflammation. Included in this aspect of the invention is thetreatment of cerebral vasculitis, multiple sclerosis, autoimmuneophthalmitis and polyneuropathia. Comprised by the invention is also theadministration of a compound of the invention for the treatment of aninflammation of the central nervous system to prevent apoptotic celldeath. Moreover, as some of the compounds of the invention show adistinct ability to induce nerve regeneration, positive treatmenteffects are often seen in central nervous system diseases involvingdamage of cells in this region. This aspect of the invention alsoincludes treatment of traumatic injuries to the central nervous system,brain edema, multiple sclerosis, Alzheimer's disease, bacterial andviral infections in the central nervous system, stroke, and haemorrhagicin the central nervous system.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases of the eye and tear glands related toinflammation. Specific examples of such diseases comprise anterior andposterior uveitis, retinal vasculitis, optic neuritis, opticneuromyelitis, Wegener's granulomatosis, Sjögren's syndrome,episcleritis, scleritis, sarcoidosis affecting the eye andpolychondritis affecting the eye.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases of the ear related to inflammation, specificexamples of which include polychondritis affecting the ear and externalotitis.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases of the nose related to inflammation, specificexamples of which are sarcoidosis, polychondritis and mid-line granulomaof the nose.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases related to inflammation of the mouth, pharynx andsalivary glands. Specific examples include Wegener's granulomatosis,mid-line granuloma, Sjögren's syndrome and polychondritis in theseareas.

Included in the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases related to inflammation in the lung. Specificexamples include treatment of idiopathic alveolitis, primary pulmonaryhypertension, bronchitis, chronic bronchitis, sarcoidosis, alveolitis ininflammatory systemic disease, pulmonary hypertension in inflammatorysystemic disease, Wegener's granulomatosis and Good Pastures' syndrome.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases related to the inflammation of the heart. Specificexamples include treatment of pericarditis, idiopathic pericarditis,myocarditis, Takayasus' arteritis, Kawasaki's disease, coronary arteryvasculitis, pericarditis in inflammatory systemic disease, myocarditisin inflammatory systemic disease, endocarditis and endocarditis ininflammatory systemic disease.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases related to inflammation of the liver. Specificexamples include treatment of hepatitis, chronic active hepatitis,biliary cirrhosis, hepatic damage by toxic agents, interferon inducedhepatitis, hepatitis induced by viral infection, liver damage induced byanoxia and liver damage caused by mechanical trauma.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases related to inflammation of the pancreas. Specificexamples include treatment (and prevention) of diabetes mellitus, acutepancreatitis and chronic pancreatitis.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases related to the inflammation of the thyroidea.Specific examples of these embodiments of the invention includetreatment of thyreoiditis, autoimmune thyreoiditis and Hashimoto'sthyreoiditis.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases related to inflammation of the kidney. Specificexamples include treatment of glomerulonephritis, glomerulonephritis insystemic lupus erythematosus, periarteritis nodosa, Wegener'sgranulomatosis, Good-Pastures' syndrome, HLAb27 associated diseases, IgAnephritis (IgA=Immunoglobulin A), pyelonephritis, chronic pyelonephritisand interstitial nephritis.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases related to the inflammation of the joints.Specific examples include treatment of Bechterew's disease, psoriaticarthritis, rheumatoid arthritis, arthritis in colitis ulcerosa,arthritis in morbus Crohn, affection of joints in systemic lupuserythematosus, systemic sclerosis, mixed connective tissue disease,reactive arthritis, Reiter's syndrome. Moreover, included in thisembodiment of the invention is treatment of arthrosis of any joint, inparticular arthrosis of finger joints, the knee and the hip.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of diseases related to the inflammation of blood vessels.Specific examples include treatment of arteritis temporalis,periarteritis nodosa, arteriosclerosis, Takayasus' arteritis andKawasaki's disease. Particularly advantageous is the capacity of somecompounds of the invention to afford protection against and preventionof arteriosclerosis. This is in part due to the capacity of somecompounds of formula (I) or the pharmacologically acceptable saltsthereof to prevent the induction of inducible nitric oxide synthesis(iNOS) caused by the action of oxidized Low Density Lipoprotein onendothelial cells and blood vessel walls.

Comprised by the invention is also the administration of a compound ofthe invention for the treatment of drug-induced disorders of the bloodand lymphoid system, including the treatment of drug-inducedhypersensitivity (including drug hypersensitivity) affecting blood cellsand blood cell forming organs (e.g. bone marrow and lymphoid tissue).Specific embodiments of this aspect of the invention include thetreatment of anemia, granulocytopenia, thrombocytopenia, leukopenia,aplastic anemia, autoimmune hemolytic anemia, autoimmunethrombocytopenia and autoimmune granulocytopenia.

The compounds of the invention may also be administered for thetreatment of fast allergic disorders (Type I allergy). Included in thisembodiment of the invention is the treatment of anaphylactic reactions,anaphylactoid reactions, asthma, asthma of allergic type, asthma ofunknown origin, rhinitis, hay fever and pollen allergy.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of inflammation related to infections of any origin. Specificexamples include treatment of inflammation secondary to infection causedby virus, bacteria, helminths and protozoae.

Comprised by the invention is also the administration of a compound offormula (I) or a pharmacologically acceptable salt thereof for thetreatment of inflammations related to trauma and/or tissue injury of anyorigin.

Compounds of formula (I) or pharmaceutically acceptable salts thereofhave valuable pharmacological properties, making them useful for thetreatment of disorders of the cardiovascular system such as disordersrelated to blood pressure, heart rate, vascular tone, natriuresis,bleeding, shock, disorders related to ischemia, infarction, repercussioninjuries, arrhythmias of the heart, in particular during ischemia, orfor the treatment of arrhythmias associated with reoxygenation of apreviously ischemic period of the heart.

Compounds of formula (I) or the pharmaceutically acceptable saltsthereof have valuable pharmacological properties, making them useful forthe treatment of pain such as pain of central origin, pain seen afterdamage to the CNS, stroke, infarction, pain of peripheral origin,chronic pain, neuropathies and disorders where a treatment effect isachieved by stimulation of receptors in the periaqueductal grey area.

Because of the capacity of compounds of the invention to stimulatepigment formation in epidermal cells, compounds of the invention may bealso useful for inducing skin tanning for cosmetic reasons, fortreatment of vitiligo, or any other condition where darkening of skincolor is desired. Moreover, because of the ability of compounds of theinvention to inhibit pigment formation in cells of the skin, they mayalso be useful for inducing lighter skin color for cosmetic reasons, orduring any condition where a lighter color of skin is desired.

Compounds of formula (I) or the pharmaceutically acceptable saltsthereof have valuable pharmacological properties, making them useful tocause skin tanning, darkening the colour of the skin, to induce melaninsynthesis in the skin, to reduce skin tanning, lightening the colour ofthe skin, to reduce or block melanin synthesis in the skin, to causeanti-inflammatory actions in the skin, to modulate epidermal growth, toimprove wound healing, to treat acne, seborrhoea, acne roseacea,conditions related to malfunctions of the glands of the skin, e.g.sebacous glands and over or underproduction of sebum.

Compounds of the invention are useful for inhibiting or stimulating thein vivo formation of second messenger elements such as cAMP. Suchinhibition/stimulation may be used in cells or crushed cell systems invitro, e.g. for analytical or diagnostic purposes.

For analytical and diagnostic purposes the compounds of the inventionmay be used in radioactive form where they comprise one or moreradioactive labels or gamma or positron emitting isotopes, to be used inradioligand binding for the quantification as well as tissuelocalisation of MC-receptors, for analysis of dissociation/associationconstants, and for imaging of in vivo binding by the use ofscintigraphy, positron emission tomography (PET) or single photonemission computed tomography (SPECT), or for the diagnosis of diseaseand treatment of any malignancy where the malignant cells contain MCreceptors.

Alternatively the compounds of the invention can be labelled with anyother type of label that allows detection of the respective compound,e.g. fluorescence, biotin, NMR, MRI, or labels activated bygamma-irradiation, light photons or biochemical processes, or by lightor UV-light (the latter in order to obtain a compound useful forcovalent labelling of MC receptors by a photoaffinity technique).

Compounds of formula (I) or the pharmacologically acceptable saltsthereof may also be tagged with a toxic agent (i.e. doxorubicin, ricin,diphtheria toxin or other) and used for targeted delivery to malignantcells bearing MC receptors, or tagged with a compound capable ofactivating the endogenous immune system for triggering the immune system(for example a compound, monoclonal antibody or other, capable ofbinding to a T-cell antigen, e.g. CD3 or other) for treatment ofmalignancies and other MC receptor expressing diseases. The thus formedhybrid compound will direct cytotoxic cells to the malignant melanomacells or the MC1-receptor bearing malignant cells and inhibit the tumorgrowth.

Compounds of formula (I) or a pharmacologically acceptable salt thereofmay be attached to the antibody chemically by covalent or non-covalentbond(s).

Compounds of the invention may be used for the treatment and diagnosisof diseases, disorders and/or pathological conditions in an animal, inparticular in man.

The present invention also relates to a pro-drug which, uponadministration to an animal or a human, is converted to a compound ofthe invention. Pro-drugs of the compounds of formula (I) and theirpharmacologically acceptable salts may be used for the same purposes asdescribed in this specification for the compounds of the invention, aswell as is disclosed in the Examples given below.

The compounds of the present invention may be bound covalently ornon-covalently to one or several of other molecule(s) of any desiredstructure(s); the thus formed modified compound or complex may be usedfor the same purposes as described in this specification for thecompounds of the invention, as well as is disclosed in the Examplesgiven below. In a particularly important embodiment of the invention, aradioactively-labeled molecule is covalently bound to a compound offormula (I) or a pharmacologically acceptable salt thereof so as to makea compound of formula (I) or a pharmacologically acceptable salt thereofradioactively labeled.

The invention also relates to uses of compounds of the invention forvarious medical and veterinary practices related to melanocytestimulating hormone receptors.

Compounds of the invention have an effect on xanthine oxidase inmammals, including humans.

Methods of Preparation

The compounds having the general formula (I) may be prepared by thefollowing general method.

Method 1.

A compound of formula (II) wherein X, R1, R2, R3, R4 and R5 are aspreviously defined, is reacted with aminoguanidine (III) or a salt orprotected form thereof wherein X is as previously defined, followed ifnecessary or desired by deprotection to yield a compound of formula (I).

EXAMPLES

The following examples are intended to illustrate but not to limit thescope of the invention, although the compounds named are of particularinterest for the intended purposes. These compounds have been designatedby a number code, a:b, where a means the number of example, wherein thepreparation of the compound is described, and b

refers to the order of the compound prepared according to that example.Thus example 1:2 means the second compound prepared according to Method1 (see example 1).

Example 1

IR, NMR, MS and elementary analysis have confirmed the structures of thecompounds. When melting points (m.p.) are given, these are uncorrected.

Preparation of Compound 1:1

A solution of 2-chloro-3,4-dimethoxybenzaldehyde (1.0 g, 5 mmol),aminoguanidine bicarbonate (0.68 g, 5 mmol) and acetic acid (1 ml), in15 ml of methanol was heated at reflux for 10 min. The reaction mixturewas cooled down to 0° C. and the residue was filtered off. The filtratewas evaporated under vacuum and the product was crystallised fromethanol. Yield of the title compound 1:1 was 1.1 g (70%), M.p. 198-200°C.

Preparation of Compounds 1:2-1:164

Compounds 1:2-1:164 were prepared using essentially the same approach asfor 1:1 by using Method 1. Compounds with their data was as follows:

-   1 N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine acetate, m.p.    198-200° C.-   2 N-(3-Bromobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    177-178.5° C.-   3 N-(3-Bromo-4-methoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 209-210.5° C.-   4 N-(5-Chloro-2-nitrobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 180-181° C.-   5 N-(2,4-Dihydroxybenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 194-195° C.-   6 N-(2,3-Dihydroxybenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 108-109° C.-   7 N-(2,4,5-Trimethoxybenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 98.5-99.5° C.-   8 N-(3-Nitrobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    204.5-206° C.-   9 N-(4,5-Methylenedioxy-2-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 108-111° C.-   10 N-(3,4,5-Trimethoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 139-141° C.-   11 N-(4-Chloro-3-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 184-187° C.-   12 N-(4-Methoxybenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    175-177° C.-   13 N-(2-Bromobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    148.5-150° C.-   14 N-(2,3,4-Trimethoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 179-181° C.-   15 N-(2-Hydroxy-4,6-dimethoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 133-135° C.-   16 N-(2,5-Dimethoxybenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 137-139° C.-   17 N-(2,3-Dimethoxybenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 91-93° C.-   18 N-(2,5-Difluorobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 186-187.5° C.-   19 N-(5-Bromo-2-hydroxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 217-218° C.-   20 N-(4-Dimethylaminobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 185.5-187° C.-   21 N-(4-Nitrobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    191-193° C.-   22 N-(2-Hydroxy-3-methoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 173-175° C.-   23 N-(3-Chlorobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    184-186° C.-   24 N-(2-Hydroxybenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    172-174° C.-   25 N-(2,3,4-Tribenzyloxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 147-149° C.-   26 N-(Benzylideneamino)guanidine acetate, m.p. 196-198° C.-   27 N-(3,4,5-Trimethoxybenzylideneamino)guanidine acetate, m.p.    223-225° C.-   28 N-(4-Chlorobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    192-194° C.-   29 N-(3,4-Methylenedioxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 204-206° C.-   30 N-(4-Bromobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    199-200° C.-   31 N-(4-Diethylaminobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 100-102° C.-   32 N-(2-Hydroxy-5-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 217-219° C.-   33 N-(4-Hydroxybenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    83-85° C.-   34 N-(2,4,6-Trimethoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 80-82° C.-   35 N-(2,3,4-Trihydroxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 100-102° C.-   36 N-(3-Hydroxy-4-methoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 88-89° C.-   37 N-(2-Nitrobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    204-206° C.-   38 N-(2-Bromo-3,4,5-trimethoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 172-175° C.-   39 N-(2,4-Dinitrobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 208-211° C.-   40 N-(2-Chloro-6-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 92-94° C.-   41 N-(3,5-Dimethoxybenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 92-95° C.-   42 N-(5-Hydroxy-2-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 182-183° C.-   43 N-(3,6-Dimethoxy-2-nitroxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 101-102° C.-   44 N-(3,4-Dimethoxy-2-chlorobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 95-97° C.-   45 N-(3,4-Dimethoxy-2-chlorobenzylideneamino)guanidine acetate, m.p.    198-200° C.-   46 N-(Benzylideneamino)-N′-hydroxyguanidine tosylate, m.p. 169-171°    C.-   47 N-(3,4-Dimethoxy-2-chlorobenzylideneamino)-N′-hydroxyguanidine    1.5 hydrochloride, m.p. 214-216° C.-   48 N-(2,3-Dimethoxy-5-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate 0.3 hydrate, m.p. 174-176° C.-   49 N-(2,3-Dimethoxy-5-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate 0.3 hydrate, m.p. 174-176° C.-   50 N-(2,3-Dimethoxy-5,6-dinitrobenzylideneamino)-N′-hydroxyguanidine    tosylate 0.15 hydrate, m.p. 178-179° C.-   51 N-(2,6-Dimethoxybenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 69-71° C.-   52 N-(2,3-Dimethoxy-6-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 81-83° C.-   53 N-(5-Bromo-2,4-dimethoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 102-105° C.-   54 N-(2-Fluorobenzylideneamino)-N′-hydroxyguanidine tosylate 0.1    hydrate, m.p. 169-171° C.-   55 N-(2-Methoxybenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    79-82° C.-   56 N-(2,4,6-Trimethoxybenzylideneamino)guanidine acetate, m.p.    66-68° C.-   57 N-(2,3-Methylenedioxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 163-164.5° C.-   58 N-(4-Bromo-3-nitrobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 201-202.5° C.-   59    N-(5-Bromo-2-hydroxy-3-methoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 131.5-134° C.-   60 N-(3-Methoxybenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    151-153.5° C.-   61 N-(2,3-Dinitro-6-chlorobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 170-172.5° C.-   62 N-(3,6-Dichloro-2-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 183-184.5° C.-   63 N-(2,6-Dinitrobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 91-93° C.-   64    N-(2-Chloro-3,4-dimethoxy-6-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 104-106.5° C.-   65 N-(2,4-Dinitrobenzylideneamino)guanidine acetate, m.p. 224-226°    C.-   66 N-(2-Chlorobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    156-158° C.-   67 N-(4-Fluorobenzylideneamino)-N′-hydroxyguanidine tosylate 0.25    hydrate, m.p. 182-184° C.-   68 N-(3-Fluorobenzylideneamino)-N′-hydroxyguanidine tosylate 0.2    hydrate, m.p. 170-171.5° C.-   69 N-(4-Cyanobenzylideneamino)-N′-hydroxyguanidine tosylate 0.2    hydrate, m.p. 203-204° C.-   70 N-(3,5-Dimethoxybenzylideneamino)-N′-hydroxyguanidine tosylate    0.5 hydrate, m.p. 131-133° C.-   71 N-(4-Fluoro-3-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 190-192.5° C.-   72 N-(2-Chloro-5-nitrobenzylideneamino)-N′-hydroxyguanidine tosylate    0.2 hydrate, m.p. 189-191° C.-   73 N-(4-Chloro-2-nitrobenzylideneamino)-N′-hydroxyguanidine tosylate    0.25 hydrate, m.p. 179-181.5° C.-   74 N-(3,4-Dichlorobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 200-202.5° C.-   75 N-(2,4-Dichlorobenzylideneamino)-N′-hydroxyguanidine tosylate 0.5    hydrate, m.p. 158-161° C.-   76 N-(4-Methoxy-3-nitrobenzylideneamino)-N′-hydroxyguanidine, m.p.    219-221° C.-   77 N-(2,3-Dichlorobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 197-199.5° C.-   78 N-(2-Fluoro-5-nitrobenzylideneamino)-N′-hydroxyguanidine tosylate    0.4 hydrate, m.p. 172-175° C.-   79 N-(2-Methoxy-5-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate 0.7 hydrate, m.p. 115-117° C.-   80 N-(4-Hydroxy-3,5-dimethoxybenzylideneamino)-N′-hydroxyguanidine    tosylate 0.4 hydrate, m.p. 114-115° C.-   81 N-(2-Bromo-5-chloro3-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 195-196.5° C.-   82 N-(3-Bromo-2,6-dinitrobenzylideneamino)-N′-hydroxyguanidine    tosylate 0.5 hydrate 1.8 propanol, m.p. 91-93° C.-   83 N-(3,5-Dinitro-2-methoxybenzylideneamino)-N′-hydroxyguanidine    tosylate 0.2 hydrate, m.p. 185-187° C.-   84 N-(5-Bromo-2-hydroxy-3-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate 0.1 hydrate, m.p. 186-189° C.-   85 N-(3-Nitrobenzylideneamino)guanidine acetate, m.p. 147-148.5° C.-   86 N-(2-Hydroxy-4,6-dimethoxybenzylideneamino)guanidine acetate,    m.p. 115-118° C.-   87 N-(4-Nitrobenzylideneamino)guanidine acetate, m.p. 184-186° C.-   88 N-(3-Methoxy-2,6-dinitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 123.5-125° C.-   89 N-(3-Bromo-4-fluorobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 204.5-206.5° C.-   90 N-(2,3-Difluorobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 186.5-187° C.-   91 N-(4-Chloro-3-fluorobenzylideneamino)-N′-hydroxyguanidine    tosylate 0.5 hydrate, m.p. 166.5-167.5° C.-   92 N-(4-Bromo-3-fluorobenzylideneamino)-N′-hydroxyguanidine tosylate    0.6 hydrate, m.p. 183-185.5° C.-   93 N-(3-Bromo-4-fluorobenzylideneamino)guanidine acetate, m.p.    172-173.5° C.-   94 N-(2,3-Difluorobenzylideneamino)guanidine acetate, m.p.    149-151.5° C.-   95 N-(4-Chloro-3-fluorobenzylideneamino)guanidine acetate, m.p.    165-171° C.-   96 N-(3-Methoxy-2,6-dinitrobenzylideneamino)guanidine hydrochloride,    m.p. 217-218° C.-   97 N-(3-Bromo-2,6-dinitrobenzylideneamino)guanidine hydrochloride,    m.p. 166.5-168° C.-   98 N-(2,3-Dimethoxy-5,6-dinitrobenzylideneamino)guanidine acetate,    m.p. 165-171° C.-   99 N-(5-Bromo-2,4-dimethoxybenzylideneamino)guanidine acetate 0.5    hydrate, m.p. 221-224° C.-   100 N-(2,3-Dimethoxy-5-nitrobenzylideneamino)guanidine acetate, m.p.    191-194° C.-   101 N-(3,4-Difluorobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 199-201° C.-   102 N-(4-Phenylbenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    171-173° C.-   103 N-(3-Chloro-2,6-dinitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 85-88° C.-   104 N-(4-Phenylbenzylideneamino)guanidine acetate, m.p. 191-194° C.-   105 N-(3,4-Difluorobenzylideneamino)guanidine acetate, m.p. 176-178°    C.-   106 N-(4-Bromo-2-fluorobenzylideneamino)-N′-hydroxyguanidine    tosylate 0.3 hydrate, m.p. 176-179° C.-   107 N-(2-Fluoro-5-nitrobenzylideneamino)guanidine acetate, m.p.    192-195° C.-   108 N-(4-Bromo-2-fluorobenzylideneamino)guanidine acetate, m.p.    187-188° C.-   109 N-(2-Bromo-5-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 148-150° C.-   110 N-(2,4-Dinitrobenzylideneamino)-N′-hydroxyguanidine    hydrochloride, m.p. 191-193° C.-   111 N-(2,6-Difluorobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 176-179° C.-   112 N-(3-Chloro-4-fluorobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 198.5-201° C.-   113 N-(3,5-Dichlorobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 208-210.5° C.-   114 N-(2-Bromo-4-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 170-173° C.-   115 N-(3,5-Dinitrobenzylideneamino)-N′-hydroxyguanidine tosylate 0.5    hydrate, m.p. 202-207° C.-   116 N-(2,3-Dinitrobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 214-216° C.-   117 N-(3,5-Dichlorobenzylideneamino)guanidine acetate, m.p. 131-134°    C.-   118 N-(3,5-Dinitrobenzylideneamino)guanidine acetate dihydrate, m.p.    251-254° C. (decomp.)-   119 N-(2,6-Difluorobenzylideneamino)guanidine acetate, m.p.    138.5-141° C.-   120 N-(3-Chloro-4-fluorobenzylideneamino)guanidine acetate, m.p.    141-144° C.-   121 N-(2-Bromo-4-nitroobenzylideneamino)guanidine acetate, m.p.    145-147° C.-   122 N-(2-Bromo-5-nitroobenzylideneamino)guanidine acetate, m.p.    205-208° C. (decomp)-   123 N-(2-Iodobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    136-139° C.-   124 N-(2-Iodobenzylideneamino)guanidine acetate, m.p. 1714-173° C.-   125 N-(2,3-Dimethoxy-5-nitrobenzylideneamino)guanidine    hydrochloride, m.p. 237-238° C.-   126 N-(2-Hydroxy-4-methoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 174-176° C.-   127 N-(2-Hydroxy-4-methoxybenzylideneamino)guanidine acetate, m.p.    161-164° C.-   128 N-(4-Bromo-3-nitrobenzylideneamino)guanidine acetate, imp.    152-153° C.-   129 N-(6-Chloro-2,3-dinitrobenzylideneamino)guanidine hydrochloride,    m.p. 153-154.5° C.-   130 N-(3-Bromo-4-methoxybenzylideneamino)guanidine hydrochloride,    imp. 261-262.5° C.-   131 N-(3-Iodobenzylideneamino)guanidine hydrochloride, imp. 203-204°    C.-   132 N-(3-Iodobenzylideneamino)-N′-hydroxyguanidine tosylate, m.p.    193.5-195° C.-   133 N-(2-Sulphobenzylideneamino)guanidine hydrochloride, m.p. >260°    C.-   134 N-(2-Sulphobenzylideneamino)-N′-hydroxyguanidine, imp.    243.5-244° C.-   135 N-(3,4-Dichlorobenzylideneamino)guanidine acetate, m.p. 138-140°    C.-   136 N-(2-Chloro-5-nitrobenzylideneamino)guanidine acetate, m.p.    222-224° C. (decomp)-   137 N-(4-Chloro-3-nitrobenzylideneamino)guanidine acetate, m.p.    136-139° C. (decomp.)-   138 N-(4-Fluoro-3-nitrobenzylideneamino)guanidine acetate, m.p.    222-224° C. (decomp.)-   139 N-(4-Methoxy-3-nitrobenzylideneamino)guanidine acetate, imp.    144-147° C.-   140    N-(2-Chloro-3,4,5-trimethoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 176-178° C.-   141 N-(3,5-Difluorobenzylideneamino)-N′-hydroxyguanidine tosylate,    m.p. 210.5-213° C.-   142 N-(5-Bromo-2,3,4-trimethoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 195-197° C.-   143 N-(3-Chloro-4-methoxybenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 204-207° C.-   144 N-(2,3-Dimethoxy-5-nitrobenzylideneamino)-N′-hydroxyguanidine    hydrochloride, m.p. 196-197.5° C.-   145 N-(3,5-Difluoro-2-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 176-178° C.-   146 N-(3,5-Dichloro-2-nitrobenzylideneamino)-N′-hydroxyguanidine    tosylate, m.p. 205-207° C.-   147 N-(3,5-Difluoro-2-nitrobenzylideneamino)guanidine acetate, m.p.    231-233° C.-   148 N-(3,5-Dichloro-2-nitrobenzylideneamino)guanidine acetate, m.p.    88-91° C.-   149 N-(2-Hydroxy-3-methoxy-5-nitrobenzylideneamino)guanidine    hydrochloride, m.p. 243-246° C.-   150 N-(2-Hydroxy-4-methoxy-5-nitrobenzylideneamino)guanidine    hemiacetate, m.p. 227-230° C.-   151 N-(3-Chloro-4-methoxy-5-nitrobenzylideneamino)guanidine acetate,    m.p. 255-258° C. (decomp.)-   152 N-(3,5-Dichloro-4-methoxybenzylideneamino)guanidine acetate,    m.p. 185-190° C.-   153 N-(3-Bromo-4-methoxy-5-methylbenzylideneamino)guanidine acetate,    m.p. 163-166° C.-   154 N-(2,3,4-Trimethoxybenzylideneamino)guanidine hydrochloride,    m.p. 181-183° C.-   155 N-(4-Chloro-2-methoxy-5-nitrobenzylideneamino)guanidine acetate,    m.p. 196-199° C.-   156 N-(3,6-Dichloro-2-nitrobenzylideneamino)guanidine acetate, m.p.    219.5-221° C.-   157 N-(2-Hydroxy-4-methyl-5-nitrobenzylideneamino)guanidine    hydrochloride, m.p. 229-230° C.-   158 N-(2-Bromo-5-chloro-3-nitrobenzylideneamino)guanidine acetate,    m.p. 136.5-137° C.-   159 N-(3-Hydroxy-4-methyl-2-nitrobenzylideneamino)guanidine acetate,    m.p. 240-241° C.-   160 N-(5-Bromo-4-methyl-2-nitrobenzylideneamino)guanidine    hydrochloride, m.p. 246.5-248° C.-   161 N-(5-Bromo-2-hydroxy-3-nitrobenzylideneamino)guanidine    hydrochloride, m.p. >250° C.-   162 N-(5-Bromo-2-methoxy-3-nitrobenzylideneamino)guanidine    hydrochloride, m.p. 258-259° C.-   163 N-(2,4-Dimethoxy-5-nitrobenzylideneamino)guanidine acetate, m.p.    207-210° C.-   164 N-(4-Bromo-2-fluoro-5-nitrobenzylideneamino)guanidine acetate,    m.p. 175-198° C. (decomp.)

Example 2

This example illustrates the potency of compounds of formula (I) andtheir therapeutically active acid addition salts for treatment of mentaldisorders.

Test 1. Affinity for the MC1-Receptor

The binding assay was carried out essentially as described by Lunec etal, Melanoma Res 1992; 2; 5-12, using I¹²⁵-NDP-αMSH as ligand.

Test 2. Affinity for the MC3-Receptors, the MC4-Receptors and theMC5-Receptors

The binding assays were carried out essentially as described bySzardenings et al, J Biol Chem 1997; 272; 27943-27948 and Schiöth et al,FEBS Lett 1997; 410; 223-228 using I¹²⁵-NDP-αMSH as ligand.

Test 3. cAMP

The stimulation of cAMP was carried out essentially as described bySchiöth et al, Br J Pharmacol 1998; 124; 75-82.

TABLE 1 Affinity for MC-receptors Ki(μM) Compound MC1 MC3 MC4 MC5 1:3 4291 62 47 1:4 42 68 61 33

TABLE 1b Influence on cAMP MC1c MC3c MC4c MC5c 1:3 8.4 16 31.8 4.7 1:46.4 1 17.1 8.7

Example 3

The following formulations are representative for all of thepharmacologically active compounds of the invention.

Example of a Preparation Comprising a Capsule

Per capsule Active ingredient, as salt  5 mg Lactose 250 mg Starch 120mg Magnesium stearate  5 mg Total up to 385 mg

In case higher amounts of active ingredient, the amount of lactose usedmay be reduced.

Example of a Suitable Tablet Formulation.

Per tablet Active ingredient, as salt  5 mg Potato starch 90 mgColloidal Silica 10 mg Talc 20 mg Magnesium stearate  2 mg 5% aqueoussolution of gelatine 25 mg Total up to 385 mg 

A solution for parenteral administration by injection can be prepared inan aqueous solution of a water-soluble pharmaceutically acceptable acidaddition salt of the active substance preferably in a concentration of0.1% to about 5% by weight. These solutions may also contain stabilisingagents and/or buffering agents.

The invention claimed is:
 1. A method of treating inflammation,comprising administering an effective amount of a compound of generalFormula (I)

wherein X is H; R1, R2, R3, R4 and R5 are the same or different and areselected from the group consisting of hydrogen, halogen, methyl,methoxy, hydroxy, nitro and sulpho; and wherein one or more of R1, R2,R3, R4 and R5 are methoxy or hydroxy; or a pharmacologically active saltthereof; to a patient in need thereof.
 2. The method of according toclaim 1, wherein one or more of R1, R2, R3, R4 and R5 are methyl.
 3. Themethod according to claim 1, wherein one or more of R1, R2, R3, R4 andR5 are halogen atoms.
 4. The method according to claim 3, wherein thehalogen is fluoro or chloro.
 5. The method according to claim 1, whereinthe compound is selected from the group consisting of: 1N-(2-chloro-3,4-dimethoxybenzylideneamino)guanidine acetate, 2N-(3,4,5-Trimethoxybenzylideneamino)guanidine acetate 3N-(3,4-Dimethoxy-2-chlorobenzylideneamino)guanidine 4N-(2,4,6-Trimethoxybenzylideneamino)guanidine acetate 5N-(2-Hydroxy-4,6-dimethoxybenzylideneamino)guanidine acetate 6N-(3-Methoxy-2,6-dinitrobenzylideneamino)guanidine hydrochloride 7N-(2,3-Dimethoxy-5,6-dinitrobenzylideneamino)guanidine acetate 8N-(5-Bromo-2,4-dimethoxybenzylideneamino)guanidine acetate 0.5 hydrate 9N-(2,3-Dimethoxy-5-nitrobenzylideneamino)guanidine acetate 10N-(2,3-Dimethoxy-5-nitrobenzylideneamino)guanidine hydrochloride 11N-(2-Hydroxy-4-methoxybenzylideneamino)guanidine acetate 12N-(3-Bromo-4-methoxybenzylideneamino)guanidine hydrochloride 13N-(4-Methoxy-3-nitrobenzylideneamino)guanidine acetate 14N-(2-Hydroxy-3-methoxy-5-nitrobenzylideneamino)guanidine hydrochloride15 N-(2-Hydroxy-4-methoxy-5-nitrobenzylideneamino)guanidine hemiacetate16 N-(3-Chloro-4-methoxy-5-nitrobenzylideneamino)guanidine 17N-(3,5-Dichloro-4-methoxybenzylideneamino)guanidine acetate 18N-(3-Bromo-4-methoxy-5-methylbenzylideneamino)guanidine acetate 19N-(2,3,4-Trimethoxybenzylideneamino)guanidine hydrochloride 20N-(4-Chloro-2-methoxy-5-nitrobenzylideneamino)guanidine acetate 21N-(2-Hydroxy-4-methyl-5-nitrobenzylideneamino)guanidine hydrochloride 22N-(3-Hydroxy-4-methyl-2-nitrobenzylideneamino)guanidine acetate 23N-(5-Bromo-2-hydroxy-3-nitrobenzylideneamino)guanidine hydrochloride 24N-(5-Bromo-2-methoxy-3-nitrobenzylideneamino)guanidine hydrochloride,and 25 N-(2,4-Dimethoxy-5-nitrobenzylideneamino)guanidine acetate, or apharmacologically acceptable salt thereof.
 6. The method according toclaim 1, wherein the compound of Formula I is present in apharmaceutical composition together with one or more adjuvants, carriersor excipients.
 7. The method according to claim 1, wherein a label, isadditionally present.
 8. The method according to claim 7, wherein thelabel is a radioactive label.
 9. The method according to claim 7,wherein the label is a toxic agent.